The brain is estimated to be made up of one hundred billion neurons which are connected by 100 trillion synapses. Synapses are the major way in which neurons communicate and therefore form the biological basis for brain function and behavior. Synapses are dynamic and changes in their structure, function and number (collectively termed plasticity) occur during learning, mediate memories, and sculpt the development of our sensory experiences. Understanding how synaptic plasticity occurs and how stable synaptic properties maintain memories throughout a lifetime is an ultimate goal in neuroscience.
One major focus of the Huber lab is to understand the cellular and molecular mechanisms which mediate synaptic plasticity. A major mechanism by which synaptic plasticity occurs is through the localized and synaptic synthesis of new proteins. Much of our work is focused on studying a form of synaptic weakening or depression which relies on very rapid, protein synthesis at synapses. Long-term synaptic depression or LTD is induced by activation of Gq coupled receptors, such as the metabotropic glutamate receptors (mGluRs). By studying the mechanisms mGluR-dependent LTD, we can address major research questions such as: How does synaptic activity regulate rapid protein synthesis at synapses? What are the proteins which are synthesized and how do they affect synapse function? What role does synaptic or dendritic protein synthesis play in the nervous system and how do alterations or dysfunction of the dendritic protein synthesis machinery contribute to neurological disease?
Altered synapse structure and dysfunction is thought to be the origin of many neurological diseases. Motivated by our basic research findings, we discovered altered synaptic plasticity and function in the mouse model of mental retardation and autism, Fragile X Syndrome. Therefore, another aim of the lab is to identify and understand how alterations in synaptic function and connectivity lead to mental retardation and autism. Specifically, we find that LTD is enhanced and abnormally regulated in a mouse model of human mental retardation, Fragile X Syndrome. Fragile X Syndrome is caused by loss of function mutations in an RNA binding protein called Fragile X Mental Retardation Protein (FMRP) which is an RNA binding protein and regulates protein synthesis at synapses. A third goal of my lab is to determine how RNA binding proteins, such as FMRP, regulate dendritic protein synthesis and, in turn, synapse function.
To address these research questions we use a multi-disciplinary approach including electrophysiology, imaging, and biochemical methods in the hippocampus and neocortex, major brain structures implicated in human cognition. Work is our laboratory is supported by grants from the NIH-NINDS and NICHD, the FRAXA Research and Autism Speaks Foundations.
RESEARCH INTERESTS
Synapse function and plasticity
Mental Retardation/ Autism/Fragile X Syndrome
G coupled neurotransmitter receptor signaling
Neocortical circuitry
Electrophysiology
RECENT PUBLICATIONS
Pfeiffer, B.E. and Huber, K.M., "Fragile X Mental Retardation Protein induces synapse loss through acute postsynaptic translational regulation" Journal of Neuroscience, 27(12):3120-30, March 2007
Waung, M.W., Pfeiffer, B.E., Nosyreva, E.D., Ronesi, J.A. and Huber, K.M., "Rapid translation of Arc/Arg3.1 selectively mediates mGluR dependent LTD through persistent increases in AMPAR endocytosis rate" Neuron, 59(1):84-97, July 2008
Gibson, J.R., Bartley, A.F., Hays, S. and Huber, K.M., "An imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of Fragile X Syndrome" Journal of Neurophysiology, 100(5):2615-26, November 2008
Ronesi, J.A. and Huber, K.M., "Homer interactions are necessary for mGluR-induced long-term depression and translational activation" Journal of Neuroscience, 28(2)::543-7, January 2008
Volk, L. J., Pfeiffer, B.E, Gibson, J.R. and Huber, K.M., "Multiple Gq-coupled receptors converge upon a common protein synthesis- dependent LTD that is affected in Fragile X syndrome mental retardation." Journal of Neuroscience, 27(43)::11624-34, October 2007
SIGNIFICANT PUBLICATIONS
Huber, K.M., Kayser, M.S. and M.F. Bear, "Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent LTD" Science, 288(5469):1254-1257, May 2000
Huber, K.M., Gallagher, S., Warren, S.T. and Bear, M.F., "Altered synaptic plasticity in a mouse model of fragile X mental retardation." Proc. Natl. Acad. Sci., 99(11):7746-7750, April 2002
Pfeiffer, B.E. and Huber, K.M., "Fragile X Mental Retardation Protein induces synapse loss through acute postsynaptic translational regulation" Journal of Neuroscience, 27(12):3120-30, March 2007
Waung, M.W., Pfeiffer, B.E., Nosyreva, E.D., Ronesi, J.A. and Huber, K.M., "Rapid translation of Arc/Arg3.1 selectively mediates mGluR dependent LTD through persistent increases in AMPAR endocytosis rate" Neuron, 59(1)::84-97, July 2008
Ronesi J.R. and Huber, K.M., "Metabotropic Glutamate Receptors and Fragile X Mental Retardation Protein: Partners in translational regulation at the synapse" Science Signaling, 1(5)::pe6, February 2008
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